Cannabinoid receptors belong to the G-protein coupled (“GPCR”) receptor superfamily. Cannabinoid receptors include at least two subtypes, referred to as CB1 and CB2, which are distinguished by their amino acid sequence, tissue distribution, signaling mechanisms, and ability to bind subtype-specific ligands. CB1 receptors are found in the central and peripheral nervous systems, while CB2 receptors are primarily expressed by cells of the immune system (Howlett (2002) Prostaglandins and other Lipid Mediators (68-69): 619-631; Pertwee et al. (2002) Prostaglandins, Leukotrienes and Essential Fatty Acids 66(2&3): 101-121; Piomelli (2003) Nature Reviews (Neuroscience) 4: 873-884.
Agonist binding to CB1 and CB2 receptors initiates signals that are transduced via Gi/o proteins coupled to the cannabinoid receptors. The transduced signals lead to inhibition of stimulus-induced adenylate cyclase, inhibition of cAMP/protein Innase A-mediated effects, and stimulation of mitogen-activated protein kinase. Agonist binding to CB1 receptors also inhibits voltage-gated Ca+2 channels and stimulates inwardly-rectifying K+ channels (Mackie et al. (1995) J. Neurosci 15(10): 6552-61). Stimulation of presynaptic CB1 receptors by agonist binding has been reported to inhibit neurotransmitter release in both the central and peripheral nervous systems (Howlett (2002) Pharmacol. Rev. 54(2): 161-202; Pertwee et al. (2002) Prostaglandins, Leukotrienes and Essential Fatty Acids 66(2&3): 101-121).
Cannabinoid receptor ligands can be characterized by both their selectivity (e.g. binding strength to cannabinoid receptors) and their specificity (e.g. relative binding strength to a CB1 receptor as compared to a CB2 receptor). Moreover, cannabinoid receptor ligands may be characterized as agonists, antagonists or inverse agonists of the receptor to which they bind. Accordingly, specific cannabinoid receptor ligands can induce profoundly different biochemical and physiological effects and, therefore, will have different therapeutic applications, as evident from the abbreviated list provided below.
For example, cannabinoids have been described as useful for the treatment of nausea and vomiting associated with administration of anti-neoplastic agents to cancer patients (Bagshaw (2002) J. Palliative Care 18(2): 111-122; Grotenhermen (2004) Neuroendocrinol. Lett. 25(1/2): 1423).
The cannabinoid system has also been reported to be directly involved in the regulation of physiological processes central to the control of appetite and body weight. Administration of cannabinoid receptor agonists has been shown to stimulate the appetite of HIV/AIDS patients afflicted with anorexia and cachexia. Administration of cannabinoid receptor antagonists/inverse agonists has been described as appetite depressants useful for the treatment and prevention of obesity (Lange et al. (2004) Curr. Opin. Drug Disc. & Devel. 7(4): 498-506; Black (2004) Curr. Opin. Investig. Drugs 5(4): 389-94; Fernandez et al. (2004) Curr. Opin. Investig. Drugs 5(4): 430-435). For example, administration of the CB1 receptor antagonist (SR 141716A) has been reported to induce a reduction in body weight and adiposity in rodents.
Cannabinoids have also been reported to be therapeutically-useful for the treatment of diseases characterized by muscle spasticity, spasm, or tremor. In particular, cannabinoids have been reported as capable of alleviating the spasticity associated with spinal cord injury and multiple sclerosis, as well as movement disorders associated with Tourette's syndrome and L-dopa-induced dyskenesia of Parkinson's disease (Grotenhermen (2004) Neuroendocrinol. Lett. 25(1/2): 14-23; Croxford (2003) CNS Drugs 17(3): 179-202).
Cannabinoid receptor agonists have been reported to attenuate pain in vivo and therefore are potentially useful for the alleviation of acute and chronic pain (Ahmad et al. (2004) Curr. Opin. Invest. Drugs 5(1): 67-70; Cichewicz (2004) Life Sciences 74: 1317-24; Walker et al. (2002) Pharmacol. Therapeut. 95: 127-135).
Cannabinoids have been reported to lower intraocular pressure, apparently via binding to intraocular CB1 receptors. Accordingly, it has been suggested in the art that such ligands may be useful for the prevention and treatment of glaucoma (Tomida et al. (2003) Br. J. Opthamol 88: 708-713). The term “glaucoma” comprises a set of diseases of the eye involving injury to the optic nerve. In certain instances, increased pressure within the eye leads to mechanical compression of and/or inhibition of blood flow to the optic nerve. The final stage of visual loss involves selective apoptosis of retinal ganglion cells as a result of compressive and/or ischemic injury to axons at the optical disc (Tomida et al. (2003) Br. J. Opthamol 88: 708-71).
Pruritus (an unpleasant sensation that prompts scratching) has been treated by phototherapy with ultraviolet B or PUVA (administration of psoralen followed by exposure of the target tissue to long-wavelength ultraviolet light), and with therapeutic agents such as naltrexone, nalmefene, danazol, and tricyclic antidepressants. More recently, administration of the cannabinoid Δ9-tetrahydrocannabinol (“Δ9-THC”) has been reported to result in a decrease in pruritus in patients who had not responded to conventional treatments (Neff et al. (2002) Am. J. Gastroenterol. 97(8): 2117-2119).
Citation of any reference in Section 2 of this application is not intended as an admission that such reference is prior art to the present application.